P1106: PRELIMINARY RESULTS OF A PHASE 1 STUDY OF NOVEL BCL-2 INHIBITOR LISAFTOCLAX (APG-2575) IN CHINESE PATIENTS (PTS) WITH RELAPSED OR REFRACTORY (R/R) NON-HODGKIN LYMPHOMAS (NHLS)
Authors: M. Sun, J. Qi, Y. Song, K. Zhou, H. Liu, A. Shen, L. Geng, F. Zhou, J. Huang, Z. Chen, H. Zhang, M. Lu, M. Ahmad, L. Men, D. Yang, Y. Zhai, J. Wang
Journal: HemaSphere (2022)

Background: Many B-cell malignancies evade apoptosis by overexpressing BCL-2 proteins. Although indicated for the management of certain hematological malignances (HMs), BCL-2 inhibitor (BCL-2i) venetoclax requires a slow dose ramp-up to reduce the risk of tumor lysis syndrome (TLS) and is associated with severe neutropenia. Investigational lisaftoclax is a novel, potent, selective BCL-2i, which was previously reported to have activity against HMs in US and Australian pts. Lisaftoclax also offers a daily (rather than weekly) ramp-up to the target dose. Aims: The objective of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of lisaftoclax in Chinese pts with R/R NHLs. Methods: In this study, pts were dosed with lisaftoclax orally once daily in 28-day cycles. A daily ramp-up schedule was used in pts with chronic lymphocyte leukemia (CLL) or NHL with medium/high-risk TLS. A regular schedule was used in pts without CLL and those with NHL with low-risk TLS. Results: As of January 1, 2022, 40 pts (median age 55.5 [range 30-79] years; 72.5% male) had been treated with lisaftoclax (dose range 20-800 mg), including 20 who remain in the trial. The median number of prior therapies was 4 (range 0-14). NHL subtypes included: 12 CLL, 9 follicular, 7 mantle cell (MCL), 4 marginal zone (MZL), 4 T-cell, 2 diffuse large B-cell, and 2 Waldenström macroglobulinemia. DLT, MTD, and laboratory/clinical TLS were not observed, and the RP2D was 600 mg. Treatment-emergent adverse events (TEAEs) were reported in 36 pts (90%), of which most were grade 1-2 (67.5%). Common TEAEs (≥ 15% all grades) were hyperuricemia (38.6%), hypertriglyceridemia and anemia (each 36.4%), thrombocytopenia (29.5%), hyperphosphatemia (27.3%), neutropenia (25%), proteinuria (22.7%), leukopenia (18.2%), and diarrhea (15.9%). Common grade 3-4 TEAEs (> 5%) were neutropenia (13.6%) and thrombocytopenia (9.1%). A total of 4 (10%) pts experienced serious AEs, including 1 small intestinal obstruction, 1 pneumonia, 1 wound hemorrhage, and 1 case each of anemia and thrombocytopenia. One pt had dose reduction because of grade 2 colitis, and 1 pt receiving 100 mg discontinued because of grade 4 thrombocytopenia. With a medium treatment duration of 4 (range 4-20) cycles, 12 of 32 (37.5%) evaluable pts reached a complete response (CR; n = 4) or partial response (PR; n = 8), including 7 with CLL, 2 MCL, 2 MZL, and 1 T-cell NHL. In pts with CLL, the overall response rate (ORR) was 63.6%, CR 27.3%, and PR rate 36.4%. At doses ≥ 200 mg, the ORR was 87.5%. A total of 8 of 11 pts had at least 1 adverse prognostic factor (TP53 mutation/17p-/IGHV unmutated/complex chromosomal abnormalities). Of 11 pts, 5 had disease that previously failed BTKi or CD20 monoclonal antibody therapy. Systemic exposure increased across lisaftoclax doses from 20 to 800 mg, with an average half-life of 4 to 6 hours. There was no significant accumulation following the once-daily dosing. Summary/Conclusion: Here, we report for the first time clinical data for lisaftoclax in Chinese pts with R/R NHLs. Lisaftoclax was well tolerated at doses of up to 800 mg/day, with no TLS observed (despite the daily ramp-up), and was active against CLL/SLL, MZL, MCL, and T-cell NHL subtypes. Lisaftoclax may offer a more convenient treatment alternative, with a daily ramp-up schedule that may be more pt friendly. ClinicalTrials.gov: NCT03913949.